The relationship between the Mediterranean diet and Axis I disorders: A systematic review of observational studies

Abstract Axis I disorders are one of the major health burdens worldwide. Evidence suggests that Mediterranean diet has key biological factors associated with reducing the progression of these disorders. This systematic review aimed to clarify the relationship between Mediterranean diet and Axis I disorders. PubMed and Scopus databases were searched from January 2016 up to June 2021. Those observational studies in English language that assessed the relationship between Mediterranean diet and Axis I disorders (such as depression, anxiety, eating disorders, schizophrenia, etc.) were included in this review. The Newcastle–Ottawa Scale was used to evaluate the quality of studies. Thirty‐six studies (15 cohorts, 19 cross‐sectional, and 2 case–control) met the inclusion criteria. The results revealed that more than two‐thirds of the studies (25 studies, 69.44%) had significant protective relationship between receiving Mediterranean diet and reducing the symptoms or incidence of Axis I disorders. Most studies were performed on depression (29 studies measured depression at least as one of the Axis I disorders), of which 72.41% reported an inverse relationship. There were also 9 studies on anxiety (studies that measured anxiety at least as one of the Axis I disorders), that 77.77% of them observed protective association. Moreover, majority of the studies (25 studies, 69.44%) had high quality, of which 76% found an inverse relationship. In conclusion, it seems that the Mediterranean diet can reduce the symptoms or the occurrence of Axis I disorders (especially depression and anxiety). However, more extensive review studies, particularly with interventional designs, are necessary to prove the result.

health problem, with its prevalence increasing sharply even in young people. Inappropriate diet, smoking, and inadequate physical activity are some of the causes of mental disorders, particularly anxiety and depression (Firth et al., 2020).
Depression is one of the most important mental disorders in different ages (especially in adulthood and elderly) and is a basis for other diseases that can have devastating effects on mental health and quality of life (Casey, 2017;Lai et al., 2017). According to the reports of World Health Organization (WHO), this disorder is expected to be one of the most common mental disorders in communities in the 2030s (Gianfredi et al., 2021). Anxiety is another common Axis I disorder that can lead to mental and functional problems as well as gastrointestinal problems, diabetes, and thyroid disorders (Masana et al., 2019). Another mental disorder that affects societies is bipolar disorder, which is less common than depression and anxiety, but is more severe and chronic. This mental disorder can impair job performance and lead to suicide (Khan et al., 2019). Schizophrenia is also a mental problem with certain complications and can increase the mortality rate by 2 to 3 times compared to the general population and put people at increased risk of cardiovascular diseases, cancer, metabolic syndrome, etc. (Charlson et al., 2018;Costa et al., 2018;Costa et al., 2019). Eating disorders, which fall into the category of Axis I disorders as well, are characterized by abnormal eating and dissatisfaction with weight and body shape (Leone et al., 2018).
Besides, obsessive-compulsive disorder causes significant changes in social and occupational functioning (Ince et al., 2017). In addition to these disorders, ADHD is one of the most common neuroviral disorders in childhood and often persists into adulthood. This feature is characterized by difficulty in maintaining attention to daily activities (San Mauro Martín et al., 2018). Post-traumatic stress disorder is also a debilitating mental disorder that occurs in a subset of people after a major traumatic event. The relevant fear can be easily activated in these people even in the absence of threats (Hori & Kim, 2019).
Considering the increasing incidence of these disorders and the heavy financial burden they impose on individuals and the public health system, preventive, rapid, and low-cost strategies to reduce the relevant consequences are essential (Lai et al., 2017). Various factors can play an important role in controlling Axis I disorders, including appropriate diet, adequate physical activity, and medications. A number of studies in recent years have shown the effective and significant role of the Mediterranean diet in the prevention and controlling of Axis I disorders (Açik et al., 2020;Recchia et al., 2020;Vall Castelló & Tubianosa, 2020). Nevertheless, in some investigations no relationship has been found between this dietary pattern and Axis I disorders (Cherian et al., 2021;Hernández-Galiot & Goñi, 2017;Masana et al., 2019).
The Mediterranean diet refers not only to the type of food consumed, but also to the lifestyle and social customs associated with the way individuals eat (Hernández-Galiot & Goñi, 2017). This diet, first described by Keys Ancel, is characterized by a high consumption of fruits, vegetables, unrefined cereals, olive oil, nuts, and seafood; moderate consumption of chicken, dairy products, and red wine; and low consumption of red meat. Adherence to this diet is associated with a reduced risk of several chronic diseases, especially cardiovascular diseases, various types of cancer, and type 2 diabetes mellitus (Mantzorou et al., 2021). The Mediterranean diet can also play a protective role against psychological disorders due to its high content of fiber, omega-3 fatty acids, vitamins B, E, magnesium, antioxidants, and phytoestrogens (Sadeghi et al., 2021). Moreover, several important components in this diet such as legumes, nuts, and fish are important factors in controlling and reducing the process of nerve damage (Hernández-Galiot & Goñi, 2017).
With regard to the prevalence of mental disorders and its association with consuming Mediterranean diet, the prevalence of depression in Spain, where Mediterranean diet is generally consumed (Moreiras-Varela, 1989), was reported to be 4.73% in 2015-2017. Based on the European Study of the Epidemiology of Mental Disorders (ESEMeD), the prevalence in Spain is lower than other countries in Europe (Vieta et al., 2021). For instance, the prevalence of depressive disorders in Germany was equal to 15.7% in 2017 (Steffen et al., 2020). It has been found that plant foods are consumed in lower amounts by Germans compared to Mediterranean residents, while the consumption of animal products is higher (Leonhäuser et al., 2004).
Therefore, due to the importance of the issue and the lack of consistency between the results obtained from primary studies, this systematic review, for the first time, aimed to evaluate the relationship between the Mediterranean diet and Axis I disorders.
Furthermore, in this review, those Mediterranean diet scores that were determined by priori approach were considered, not those Mediterranean dietary patterns that were derived from factor analysis, or in other words from posteriori approach.

| ME THODS
The Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guideline was used for conducting this systematic review (Moher et al., 2009).

| Search strategy and study selection
PubMed and SCOPUS online databases were used to search for published articles. The time span of the literature search was a 5-year period from January 1, 2016 to June 18, 2021. The search strategy was developed according to medical subject heading (MeSH) terms.
General terms used in the search strategy included depression, bipolar disorder, anxiety, schizophrenia, psychosis, obsessive-compulsive symptom, attention-deficit/hyperactivity disorder, post-traumatic stress disorder, eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and Mediterranean diet. The complete search strategy is available in Appendix A.
Those observational studies (cohort, cross-sectional, and casecontrol studies) that were published in English language and had available full-texts were included in the present systematic review.
Besides, those studies that were conducted in children or adolescents (age <18 years), or derived the Mediterranean dietary pattern from factor analysis (a statistical method that is different from direct scoring), were excluded from this review. PECOS were as follows: Participants: all individuals, except children and adolescents; Exposure: Mediterranean diet; Control group: any control group; Outcomes: Axis I disorders including depression, bipolar disorder, anxiety, schizophrenia, psychosis, obsessivecompulsive symptom, attention-deficit/hyperactivity disorder, post-traumatic stress disorder, and eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder); Study design: cohort, cross-sectional, and case-control studies.
The retrieved studies were screened by titles and abstracts for eligibility. Afterwards, full-texts of the articles that did not provide enough information according to title and abstract were assessed by two independent reviewers and discrepancies were resolved through discussion.

| Data extraction
Two authors independently extracted data from the articles and discussed in case of disagreement. This information included name of the first author, date of publication, the country in which the study was conducted, the characteristics of the participants, gender, age, sample size, method of assessing the exposure (Mediterranean diet), method of assessing the outcome, follow-up duration (for cohort studies), and the results obtained. Most of these studies used measures of associations (such as odds ratio or hazard ratio) to explore the relationship between Mediterranean diet and Axis I disorders.

| Quality assessment
The Newcastle-Ottawa Scale (NOS) was used to evaluate the overall quality of studies (cohort, cross-sectional, and case-control studies).
The NOS checklist consists of selection, comparability, and exposure/outcome sections. Each section was assigned maximum of four, two, and three points, respectively, for case-control or cohort studies; and five, two, and three points, respectively, for cross-sectional studies. According to NOS thresholds, the studies were categorized into good, fair, and poor quality (Stang, 2010). The quality assessment was performed independently by two authors and disagreements were resolved by consensus.

| RE SULTS
A total of 1050 articles were found in initial search, leaving 792 articles after removing duplicates (258 items). After screening by title and abstract, another 719 articles were deleted and 73 articles remained for full-text evaluation. Out of 73 articles, 36 studies had inclusion criteria and 37 other articles were excluded for the following reasons: 7 articles due to research on children or adolescents, 5 articles due to non-English language, 2 articles due to the use of factor analysis method, 11 articles due to the lack of evaluating the relevant exposure or outcome, 10 articles due to not being original, 1 article due to being protocol study, and 1 article due to having interventional design. The selection procedure of the studies can be found in Figure 1.

| Characteristics of studies
Tables 1 and 2 summarize the study characteristics of the included articles. Of the 36 articles included in this systematic review, 15 were cohort, 19 were cross-sectional, and 2 were a case-control study. Of these articles, most of them (29 studies, 80.56%) were conducted in Europe. In terms of gender, most studies (29 studies, 80.56%) were performed on both sexes and the mean age of the participants varied from 21.42 to 92.7 years. The sample size range for the cohort studies was 273-167,698, for the cross-sectional studies was 79-4470, and for the case-control studies was 141-273.
Evaluation of the exposure variable (i.e., the Mediterranean diet) was mostly calculated by the 11-item Mediterranean diet score (MDS; score range 0-55; 13 studies) and the 9-item Mediterranean diet score (score range 0-9; 7 studies). Evaluation of the outcome variable, which included Axis I disorders, was also measured by specific instruments. For example, depression was assessed by scales such as the Center for Epidemiologic Studies Depression Scale Besides, Spielberger State-Trait Anxiety Inventory (STAI) was one of the questionnaires used to assess anxiety (2 studies). The duration of cohort follow-ups was also varied from 12 months to 14 years.

| Findings
Out of 36 eligible studies, 25 articles (69.44%) found an inverse relationship) significant protective effect) between the Mediterranean diet and Axis I disorders, 9 studies (25%) showed no significant association, and 1 article (2.78%) showed a direct relationship (significant detrimental effect). Moreover, one study (2.78%), which evaluated anxiety and depression simultaneously, reported a significant protective relationship between anxiety and the Mediterranean diet and a significant direct association between depression and the Mediterranean diet.
In terms of study design, among the 15 cohort studies, 11 (73.33%) showed significant protective association and 4 (26.67%) showed nonsignificant relationship between the Mediterranean diet and Axis I disorders. Out of 19 cross-sectional studies, 12 studies (63.16%) found significant protective relationship, 5 studies (26.32%) found nonsignificant results, 1 article (5.26%) showed a significant direct relationship between Mediterranean diet and trait-anxiety, and 1 article (5.26%) showed a significant protective relationship between anxiety and the Mediterranean diet and a significant direct relationship between depression and the Mediterranean diet. The 2 case-control studies also showed significant protective relationship.
Out of 15 cohort studies, 14 studies examined the relationship between the Mediterranean diet and depression, and 1 study examined the relationship between this diet and eating disorders. Of the 14 cohort studies related to depression, 10 studies showed a significant protective relationship and 4 studies showed a nonsignificant relationship. In the one study that assessed eating disorders, protective relationship was observed.
Out of 19 cross-sectional studies, 9 studies examined the relationship between the Mediterranean diet and depressive disorder, 5 studies examined the relationship between this diet and depression and anxiety, 4 studies examined the relationship between the Mediterranean diet and anxiety, and 1 study examined the association between the diet and schizophrenia. Out of 9 cross-sectional studies related to depression, 6 showed a significant protective relationship and 3 found a nonsignificant association. Out of 4 crosssectional studies related to anxiety, 2 studies showed a significant protective association, 1 study showed a nonsignificant relationship, and 1 study showed a significant direct relationship. Of the 5 crosssectional studies on anxiety and depression, 4 showed significant protective associations between depression and anxiety, and 1 showed a significant protective relationship between anxiety and the Mediterranean diet and a significant direct relationship between depression and the Mediterranean diet. Moreover, the cross-sectional study examining the association between the Mediterranean diet and schizophrenia reported a non-significant relationship. Besides, one case-control study was conducted on bipolar patients and showed a significant protective relationship, and one case-control study was performed on depressive disorder and found a significant protective association. Therefore, among all the studies that examined the relationship between the Mediterranean diet and depression, 72.41% showed a significant protective relationship, 24.14% reported a non-significant association, and 3.45% found a significant direct relationship. Additionally, among the studies that examined the relationship between the Mediterranean diet and anxiety, 77.8% showed a significant protective relationship, 11.1% found a nonsignificant association, and 11.1% reported a significant direct relationship. Furthermore, the only study on eating disorders and the only study on bipolar disorder reported significant protective relationships and the only study on schizophrenia showed a nonsignificant association.

| Quality of studies
Results from the quality assessment of the studies indicated that 25 studies (69.44%) had good quality, 10 studies (27.78%) had poor quality, and only 1 study (2.78%) had fair quality. Of the high-quality studies, 19 (76%) articles showed significant protective relationships between the Mediterranean diet and axis I disorders, and 1 study found protective relationship with anxiety and direct relationship F I G U R E 1 Flow diagram of the literature search process and selection of articles

| DISCUSS ION
Considering the high prevalence of mental disorders in modern societies, applying strategies to prevent serious psychological problems is crucial. Diets such as the Mediterranean diet may help to control the progression of mental disorders (Bastos et al., 2020). As a result, a systematic review was conducted to determine the relationship between the Mediterranean diet and Axis I disorders.   can affect the brain serotonin pathway and thus can be effective in eating disorders (Bertoli et al., 2015). Additionally, some components of the Mediterranean diet such as increased monounsaturated fatty acids' intake compared to saturated fatty acids and increased omega-3 consumption can help to manage anorexia nervosa and bulimia nervosa (Leone et al., 2018).
Inflammatory processes as well as oxidative stress and mitochondrial dysfunction are also linked to the pathogenesis of bipolar disorder. As a result, adherence to the Mediterranean diet may serve as a protective factor in this Axis I disorder through reversing these conditions (Łojko et al., 2018). Mediterranean diet can be suggested in schizophrenia as well. Comorbidities, such as obesity, cardiovascular diseases, and metabolic syndrome, are usually present along with schizophrenia. Furthermore, some medications used in this mental disorder can induce weight gain. Mediterranean diet may prevent weight gain, promote weight loss, and ameliorate lipid profile, hypertension, and insulin resistance (components of metabolic syndrome) in schizophrenic patients (Groszewska et al., 2015).
As mentioned earlier, more than two-thirds of the studies in the present review observed protective associations between the Mediterranean diet and Axis I disorders. However, some studies did not achieve significant results, and even two studies found a direct relationship between receiving Mediterranean diet and increasing these disorders. One was a cross-sectional study (Vassou et al., 2021) that found positive correlation between Mediterranean diet and depression. However, the correlation between anxiety and the dietary pattern was negative. The justification of this study for the unexpected finding was that because depression is usually more severe and discernable than anxiety, depressive patients may promptly seek therapeutic strategies including adopting a healthy diet and change their nutritional habits. The other study was also cross-sectional (Carlos et al., 2020) and found a direct relationship between adherence to Mediterranean diet and trait-anxiety. The study explained that this result could have been due to an association between obsession with healthy eating and anxiety problems. has also evaluated the short-term effects of the Mediterraneanstyle dietary pattern on anxiety, cognition, and mood and implied that this dietary pattern could be an encouraging approach for improving mental well-being (Esgunoglu et al., 2021). Besides, a narrative review has pointed to the supportive role of Mediterranean diet in patients with bipolar disorder. High consumption of sugar, fat, and carbohydrate, which are common among these patients, may negatively affect mental health, whereas Mediterranean diet with a high content of fruits, vegetables, and fish can reduce inflammation and oxidative stress in bipolar patients (Beyer & Payne, 2016).
Among the strengths of this study are the novelty of this topic and the inclusion of most mental disorders in a single study and also a detailed search in the form of a systematic review. However, the present review has some limitations. For instance, the time span of the literature search was limited to 5 years, only two databases were included, and no meta-analysis was performed on the data. Another limitation was that substance use was not included as an Axis I disorder in this systematic review. Because this disorder is somewhat different to other disorders in terms of direct contact with external physical stimulants, and also because so many drugs and solvents can be categorized into this group (Nutt et al., 2007) which make it difficult to do a comprehensive search.
It is suggested that in the future, more review studies be conducted with a wider time span of literature search, on various diets, and on different age groups (including children) to examine the diets' associations with Axis I disorders. Conducting a systematic review or meta-analysis in the field of interventional studies can also have a significant impact on controlling and preventing these disorders.

| CON CLUS ION
It seems that the Mediterranean diet can be a practical diet in the control of Axis I disorders (especially depression and anxiety) and can have protective effects in this regard. Therefore, patients with Axis I disorders, including those who are not suitable for pharmacotherapy or psychotherapy, can utilize this diet as an alternative or complementary treatment. Future systematic reviews should focus on understanding the efficacy of different dietary patterns on these disorders. There is also a fundamental need to better educate individuals and physicians with the role of diets and nutrients in maintaining mental health.

ACK N OWLED G M ENTS
We do not have any acknowledgements for this review article.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

E TH I C A L A PPROVA L
This study does not involve any human or animal testing.